Monovalent Cation Permeability Research Articles

Characterization of human Aquaporin ion channels in a yeast expression system as a tool for novel ion channel discovery.

Aquaporin (AQP) channels found in all domains of life are transmembrane proteins which mediate passive transport of water, glycerol, signaling molecules, metabolites and charged solutes. Discovery of new classes of ion-conducting AQP channels has been slow, likely reflecting time- and labor-intensive methods required for traditional electrophysiology. Work here defines a sensitive mass-throughput system for detecting AQP ion channels, identified by rescue of cell growth in the K+-transport-defective yeast strain CY162 following genetic complementation with heterologously expressed cation-permeable channels, using the well characterized human AQP1 channel for proof of concept. Results showed AQP1 conferred transmembrane permeability to cations which rescued survival in CY162 yeast. Comprehensive testing showed that growth response properties fully recapitulated AQP1 pharmacological agonist and antagonist profiles for activation, inhibition, dose-dependence, and structure-function relationships, demonstrating validity of the yeast screening tool for AQP channel identification and drug discovery efforts. This method also provided new information on divalent cation blockers of AQP1, pH sensitivity of antagonists, and ion permeability of human AQP6. Site-directed mutagenesis of AQP1 channel regulatory domains confirmed that yeast growth rescue was mediated by the introduced channels. Optical monitoring with a lithium-sensitive photoswitchable probe in living cells independently demonstrated monovalent cation permeability of AQP1 channels in yeast plasma membrane. Ion channel properties of AQP1 expressed in yeast were consistent with those of AQP1 expressed in Xenopus laevis oocyte and K+-transport defective Escherichia coli. Outcomes here establish a powerful new approach for efficient screening of phylogenetically diverse AQPs for yet untested functions as cation channels.

UiO-66 membranes with confined naphthalene disulfonic acid for selective monovalent ion separation

The selective separation of monovalent ions remains a challenge because of the similar sub-nanometer sizes. Metal-organic frameworks (MOFs) are promising candidate membranes for ion selective separation based on the angstrom sized windows for size sieving. Here, to further enhance the monovalent ion selectivity, 1, 5-naphthalenedisulfonic acid tetrahydrate (NTDS) molecules with sulfonate groups are incorporated to offer a binding affinity, generating a UiO-66@NTDS membrane via the window-cavity structure confinement. In addition to the size sieving effect, the charge and affinity interaction can compensate the energy loss induced by the ion dehydration. Thus, the UiO-66@NTDS membranes exhibit elevated separation performance compared to the original UiO-66 membranes under the concentration gradient driven, accompanied by high monovalent cation permeation rates (i.e., 0.3–0.7 mol m−2 h−1) and mono-/divalent cation selectivities (i.e., ∼73 for K+/Mg2+, ∼57 for Na+/Mg2+, and ∼46 for Li+/Mg2+). This work provides guidelines for the development of efficient ion-selective MOF membranes via the combination of size sieving and interaction attraction.

Janus membrane with tailored upper and lower surface charges for ion penetration manipulation in high-performance nanofiltration

Conventional homogeneously charged nanofiltration (NF) membranes showed limited capabilities in ion transmembrane behavior control, which hindered the ion separation performances. In this study, novel Janus membranes were developed to manipulate the penetration of monovalent and divalent ions in NF. Graphene oxide nanosheets with enhanced positive charge (PGO) and negative charge (NGO) were successfully synthesized and assembled in designed orders and proportions to construct the Janus membranes with desired upper and lower surface charges. The positively charged upper surface and the negatively charged lower surface of the PN Janus membrane showed high retention of divalent cations but high permeation of monovalent cations; when the mass ratio of PGO to NGO was 1–5, the PN-1/5 membrane indicated a significant Li+/Mg2+ separation factor at 23.5. On the other hand, the NP-4/2 Janus membrane composed of negatively charged upper layer and positively charged lower layer indicated the most promising indiscriminate divalent ion removal efficiency (>80%) as compared with the literature. The molecular dynamics simulation theoretically proved the ion penetration behavior manipulation by the Janus membranes were feasible. This study proposed a facile strategy to dramatically improve the performances of NF in Mg2+/Li+ separation and indiscriminate divalent ion removal.

Optimizing functional layer of cation exchange membrane by three-dimensional cross-linking quaternization for enhancing monovalent selectivity

Monovalent cation perm-selective membrane (MCPMs) allow fast and selective transport of monovalent cations, and they are promisingly required for extraction of special ions, such as lithium extraction, acid recovery and sea salt production. Herein, we report a novel strategy to design the critical functional layers of MCPMs with both space charge repulsion and cross-linked dense screenability. The in-situ deposition polymerization of pyrrole was carried out on the surface of sulfonated polyphenyl sulfone (SPPSU) substrate membrane followed by cross-linking quaternization of the polypyrrole (PPy) layer with diiodinated functional molecules, thus, the membrane obtained more excellent selective permeability and stable transport properties of monovalent cations. It confirms that the designed PPy layers with charged surface and cross-linking structure improved the hydrophilicity, facilitated cation transport and increased ion flux. Meanwhile, for the dense PPy layer, the charged cross-linked structure endowed the functional layer with the synergistic characteristics of Donnan exclusion and pore size sieving for positively charged ions, which improved the monovalent cation perm-selectivity of the membranes. At a constant current density of 5.1 mA/cm2, the optimal membrane exhibited superior perm-selectivity (PMgNa=2.07) and monovalent cation flux (JNa+ = 2.80 × 10 −8 mol cm−2 s−1) during electrodialysis.

Efficient Ion Sieving in Covalent Organic Framework Membranes with Sub-2-Nanometer Channels.

Membranes of sub-2-nanometer channels show high ion transport rates, but it remains a great challenge to design such membranes with desirable ion selectivities for ion separation applications. Here, covalent organic framework (COF) membranes with a channel size of ≈1.4nm and abundant hydrogen bonding sites, exhibiting efficient ion sieving properties are demonstrated. The COF membranes have high monovalent cation permeation rates of 0.1-0.2mol m-2 h-1 and extremely low multivalent cation permeabilities, leading to high monovalent over divalent ion selectivities for K+ /Mg2+ of ≈765, Na+ /Mg2+ of ≈680, and Li+ /Mg2+ of ≈217. Experimental measurements and theoretical simulations reveal that the hydrogen bonding interaction between hydrated cations and the COF channel wall governs the high selectivity, and divalent cations transport through the channel needs to overcome higher energy barriers than monovalent cations. These findings provide an effective strategy for developing sub-2-nanometer sized membranes with specific interaction sites for high-efficiency ionic separation.

PVA-Based Mixed Matrix Membranes Comprising ZSM-5 for Cations Separation.

The traditional ion-exchange membranes face the trade-off effect between the ion flux and perm-selectivity, which limits their application for selective ion separation. Herein, we amalgamated various amounts of the ZSM-5 with the polyvinyl alcohol as ions transport pathways to improve the permeability of monovalent cations and exclusively reject the divalent cations. The highest contents of ZSM-5 in the mixed matrix membranes (MMMs) can be extended up to 60 wt% while the MMMs with optimized content (50 wt%) achieved high perm-selectivity of 34.4 and 3.7 for H+/Zn2+ and Li+/Mg2+ systems, respectively. The obtained results are high in comparison with the commercial CSO membrane. The presence of cationic exchange sites in the ZSM-5 initiated the fast transport of proton, while the microporous crystalline morphology restricted the active transport of larger hydrated cations from the solutions. Moreover, the participating sites and porosity of ZSM-5 granted continuous channels for ions electromigration in order to give high limiting current density to the MMMs. The SEM analysis further exhibited that using ZSM-5 as conventional fillers, gave a uniform and homogenous formation to the membranes. However, the optimized amount of fillers and the assortment of a proper dispersion phase are two critical aspects and must be considered to avoid defects and agglomeration of these enhancers during the formation of membranes.

Control of Ion Transport in Sulfonated Mesoporous Polymer Membranes

We investigated proton conductivity and the permeability of monovalent cations across sulfonated mesoporous membranes (SMMs) prepared with well-defined pore sizes and adjustable sulfonic acid content. Mesoporous membranes with three-dimensionally continuous pore structure were produced by the polymerization-induced microphase separation (PIMS) process involving the reversible addition-fragmentation chain transfer (RAFT) copolymerization of styrene and divinylbenzene in the presence of a polylactide (PLA) macrochain transfer agent and subsequent PLA etching. This allowed us to control pore size by varying PLA molar mass. Postsulfonation of the mesoporous membranes yielded SMMs whose pore structure was retained. The sulfonic acid content was adjusted by reaction time. While proton conductivity increased with increasing ion exchange capacity (IEC) without noticeable dependence on the pore size, ion permeability was strongly influenced by the pore size and IEC values. Decreasing pore size and increasing IEC resulted in a decrease in ion permeability, suggesting that ions traverse across the membrane via the vehicular mechanism, through the mesoporous spaces filled with water. We further observed that the permeability of the vanadium oxide ion was dramatically suppressed by reducing the pore size below 4 nm, which was consistent with preliminary vanadium redox flow battery data. Our approach suggests a route to developing permselective membranes by decoupling proton conductivity and ion permeability, which could be useful for designing separator materials for next-generation battery systems.

Inhibition of Ion Transport through Gramicidin A Channels by the Addition of Local Anesthetic Procaine

AbstractThe blocking effects of the cationic procaine, a typical local anesthetic (LA), on ion transport through gramicidin A (gA) channels between two aqueous phases (W1 and W2) were electrochemically elucidated. Although the gA channels promoted the permeation of monovalent cations, especially Cs+, the addition of procaine to W1 decreased the permeation of Cs+ through these channels from W1 to W2. This can be explained based on the following mechanism. Hydrophobic cationic procaine tends to approach the pore of a gA channel. Since it is too large to enter the pore, it cannot pass through the channel. Thus, cationic procaine inhibits the permeation of Cs+ from W1 to W2 by competing with Cs+ for access to the entrances of the gA channels. It is postulated that the decrease in the apparent activity of Cs+ caused by this competition prevents ion transport through the gA channels.

Reverse osmosis membranes based on a supported lipid bilayer with gramicidin A water channels

This study presents the fabrication of a biomimetic reverse osmosis (RO) membrane from a supported lipid bilayer (SLB) and gramicidin A (GA) onto polymeric substrates via electrostatic interaction and by applying hydraulic pressure. GA, a cation-selective ionophore, has high permeability for water molecules and monovalent cations in a lipid bilayer, and was therefore used as a water channel molecule. Cationic liposomes containing GA were electrostatically adsorbed onto an anionic polymeric nanofiltration membrane. The adsorbed liposomes were ruptured by applying hydraulic pressure and transformed into flat lipid bilayers. SLB formation was confirmed by salt rejection measurement and fluorescence recovery after photobleaching. The defect-free SLB was formed on the polymeric nanofiltration membrane by applying over 0.15MPa pressure. Phosphorus quantification showed that the formed SLB was not composed of a single lipid bilayer but approximately six lipid bilayers. GA incorporation into the SLB and control of the GA conformation on the SLB effectively improved water permeability. Moreover, the GA-incorporated SLB showed high NaCl rejection (>97%). Monovalent cations, Na+ ions, were rejected to maintain electric neutrality. The formed SLB showed hydraulic pressure resistance and high salt rejection at adequate levels for RO membranes.

Osmotically-driven transport in carbon nanotube porins.

We report the measurements of transport of ions and uncharged species through carbon nanotube (CNT) porins--short segments of CNTs inserted into a lipid bilayer membrane. Rejection characteristics of the CNT porins are governed by size exclusion for the uncharged species. In contrast, rejection of ionic species is governed by the electrostatic repulsion and Donnan membrane equilibrium. Permeability of monovalent cations follows the general trend in the hydrated ion size, except in the case of Cs(+) ions.

Paradoxical One-ion Pore Behavior of the Long β-Helical Peptide of Marine Cytotoxic Polytheonamide B

The cytotoxic 48-mer peptide, polytheonamide B (pTB), from a marine sponge forms a β6.3-helix with an inner diameter of 4 Å and a length of 45 Å, features that allow the selective permeation of monovalent cations across targeted cell membranes. To characterize this long, narrow pore, electrophysiological examination using a planar lipid bilayer method was performed. The single-channel current amplitude exhibited saturation for concentrated Cs+ or K+ solution, and the reversal potential in mixed solutions did not exhibit any anomalous mole-fraction behavior. These results suggest the one-ion permeation mechanism. This is in contrast to the short (26 Å) β6.3-helical gramicidin channel, which holds two ions simultaneously. The paradoxical one-ion permeation through the long pTB channel was modeled with a discrete-state Markov model. Ions permeate through the channel by stepping between two binding sites in the pore, but never occupy these sites simultaneously in either pure or mixed ion solution.

Assessing Time-Dependent Changes in Relative Ca2+ Permeability using Patch Clamp Photometry

Time-dependent changes in monovalent cation permeability have been reported for P2XR, TRPV1 and TRPA1. An important physiological question is whether relative Ca2+ permeability (PCa/PNa) also changes during prolonged agonist exposure. Previous evidence obtained using current reversal potential (ERev) measurements suggests this to be the case for TRPV1, but it is not known for P2XRs. In our hands, both TRPV1- and P2X-transfected HEK293 cells exhibited time-dependent changes in N-methyl-D-glucamine permeability during prolonged exposure to capsaicin (10 microM) or ATP (30 microM) respectively, which occurred immediately and was complete within 10-15 s. Next we used patchclamp photometry to study time-dependent changes in fractional Ca2+ current (Pf%). These experiments were problematic due to Ca2+ entry often saturating the pipette Ca2+ chelator, fura-2, even under conditions of low external Ca2+. Nevertheless, in experiments where fura-2 saturation did not occur within the first 5-10 seconds of stimulus, the relationship between total charge influx and change in fura-2 fluorescence was linear for both channels, providing no obvious evidence for PCa/PNa changes over this time scale. We considered that saturation of intracellular Ca2+ chelators such as EGTA would likely hinder assessment of time-dependent changes in PCa/PNa using ERev measurements, as these assume that the transmembrane Ca2+ concentration ratio remains constant throughout. In 10 mM external Ca2+, we performed patchclamp photometry using pipettes containing 10 mM fura-2. Cells expressing TRPV1 were stimulated with capsaicin for 25 s, with 140 mV ramps applied every 500 ms. We observed a shift in ERev for the capsaicin-evoked current from 12.2±1.9 to 1.1±1.3 mV (n=4), but this was mostly apparent after the rapid saturation of fura-2 by TRPV1-mediated Ca2+ entry. Therefore, caution is strongly encouraged when interpreting time-dependent changes in Ca2+ permeability based on ERev experiments alone.

Claudin-4 forms a paracellular barrier, revealing the interdependence of claudin expression in the loose epithelial cell culture model opossum kidney cells.

The effect of claudins on paracellular fluxes has been predominantly studied in either Madin-Darby canine kidney (MDCK) or LLCPK cells. Neither model system has a very low transepithelial resistance (TER) as observed in leaky epithelia. Moreover, results from one model system are not always consistent with another. Opossum kidney (OK) cells form tight junctions yet have a very low TER. We therefore set out to characterize the paracellular transport properties of this cell culture model. Ussing chamber dilution potential measurements revealed that OK cells exhibit a very low TER (11.7 ± 1.4 Ω·cm(2)), slight cation selectivity (P(Na)/P(Cl) = 1.10 ± 0.01), and the Eisenman permeability sequence IV; the permeability of monovalent cations ranking K(+) > Cs(+) > Rb(+) > Na(+) > Li(+). Quantitative real-time PCR studies found that OK cells endogenously express claudin-4 > -1 > -6 > -20 > -9 > -12 > -11 > -15. Overexpression of claudin-4 significantly increased TER, decreased Na(+) and Cl(-) permeability, and increased levels of claudin-1, -6, and -9 mRNA. Knockdown of claudin-4 in the overexpressing cells significantly decreased TER without altering claudin expression; thus claudin-4 forms a barrier in OK cells. Knockdown of endogenous claudin-4 decreased claudin-1, -9, and -12 expression without altering TER. Claudin-2 overexpression decreased TER, significantly increased Na(+) and Cl(-) permeability, and decreased claudin-12 and -6 expression. Together these results demonstrate that claudin expression is tightly coupled in OK cells.

Identification of TRPM5 Ion Channels in Type-II Taste Cells of Mice

TRPM5 are ion channels belonging to the TRP family, which demonstrate a nonselective permeability for monovalent cations and are activated by an increase in the intracellular calcium level. TRPM5 are present in taste receptor cells of type II responsible for reception of bitter, sweet, and umami taste sensations. Knockout of the trpm5 gene in mice results in a nearly complete loss of sensitivity to taste stimuli of the above-mentioned modalities (taste blindness). The physiological activity of TRPM5 in taste receptive cells has practically not been studied. Using a patch-clamp technique, we carried out a comparative analysis of the properties of recombinant TRPM5 and Ca2+-activated membrane channels in type-II taste cells in mice. Dialysis of the studied cells with a high-Ca2+ solution and application of a calcium ionophore, ionomycin, caused activation of outward-rectification ion channels permeable for Na+, Cs+, and K+ in CHO-strain cells with exogenous TRPM5. These channels were blocked by 100 μM triphenylphosphine oxide (TPPO). Calcium-activated channels in type-II taste cells also possessed analogous properties. Application of the calcium ionophore ionomycin or a stepwise increase in the intracellular Ca2+ level using photolysis (uncaging) caused activation of channels nonselective with respect to Na+ and Cs+ and impermeable for N-methyl-D-glucamine (NMDG+). These channels had the current–voltage characteristics of outward rectification and a high thermosensitivity (Q10 = 6.7 ± 0.5); they could be blocked by TPPO. It should be emphasized that TRPM5 were specific with respect to type-II cells. An increase in the intracellular calcium level induced the appearance of Cl– current in type-I cells and did not influence the basic current in type-III cells.

Electrophysiological properties of heteromeric TRPV4–C1 channels

We previously reported that TRPV4 and TRPC1 can co-assemble to form heteromeric TRPV4–C1 channels [12]. In the present study, we characterized some basic electrophysiological properties of heteromeric TRPV4–C1 channels. 4α-Phorbol 12,13-didecanoate (4α-PDD, a TRPV4 agonist) activated a single channel current in HEK293 cells co-expressing TRPV4 and TRPC1. The activity of the channels was abrogated by a TRPC1-targeting blocking antibody T1E3. Conductance of the channels was ~95pS for outward currents and ~83pS for inward currents. The channels with similar conductance were also recorded in cells expressing TRPV4–C1 concatamers, in which assembled channels were expected to be mostly 2V4:2C1. Fluorescence Resonance Energy Transfer (FRET) experiments confirmed the formation of a protein complex with 2V4:2C1 stoichiometry while suggesting an unlikeliness of 3V4:1C1 or 1V4:3C1 stoichiometry. Monovalent cation permeability profiles were compared between heteromeric TRPV4–C1 and homomeric TRPV4 channels. For heteromeric TRPV4–C1 channels, their permeation profile was found to fit to Eisenman sequence VI, indicative of a strong field strength cation binding site, whereas for homomeric TRPV4 channels, their permeation profile corresponded to Eisenman sequence IV for a weak field strength binding site. Compared to homomeric TRPV4 channels, heteromeric TRPV4–C1 channels were slightly more permeable to Ca2+ and had a reduced sensitivity to extracellular Ca2+ inhibition. In summary, we found that, when TRPV4 and TRPC1 were co-expressed in HEK293 cells, the predominate assembly type was 2V4:2C1. The heteromeric TRPV4–C1 channels display distinct electrophysiological properties different from those of homomeric TRPV4 channels.

Properties of the TRPML3 Channel Pore and Its Stable Expansion by the Varitint-Waddler-causing Mutation

TRPML3 is a H(+)-regulated Ca(2+) channel that shuttles between intracellular compartments and the plasma membrane. The A419P mutation causes the varitint-waddler phenotype as a result of gain-of-function (GOF). The mechanism by which A419P leads to GOF is not known. Here, we show that the TRPML3 pore is dynamic when conducting Ca(2+) to change its conductance and permeability, which appears to be mediated by trapping Ca(2+) within the pore. The pore properties can be restored by strong depolarization or by conducting Na(+) through the pore. The A419P mutation results in expanded channel pore with altered permeability that limits modulation of the pore by Ca(2+). This effect is specific for the A419P mutation and is not reproduced by other GOF mutations, including A419G, H283A, and proline mutations in the fifth transmembrane domain. These findings describe a novel mode of a transient receptor potential channel behavior and suggest that pore expansion by the A419P mutation may contribute to the varitint-waddler phenotype.

Agonist-Induced Changes in Ca2+ Permeation through the Nociceptor Cation Channel TRPA1

The Ca2+-permeable cation channel TRPA1 acts as an ionotropic receptor for various pungent compounds and as a noxious cold sensor in sensory neurons. It is unclear what proportion of the TRPA1-mediated current is carried by Ca2+ ions and how the permeation pathway changes during stimulation. Here, based on the relative permeability of the nonstimulated channel to cations of different size, we estimated a pore diameter of ∼11 Å. Combined patch-clamp and Fura-2 fluorescence recordings revealed that with 2 mM extracellular Ca2+, and at a membrane potential of −80 mV, ∼17% of the inward TRPA1 current is carried by Ca2+. Stimulation with mustard oil evoked an apparent dilatation of the pore of 3 Å and an increase in divalent cation selectivity and fractional Ca2+ current. Mutations in the putative pore that reduced the divalent permeability and fractional Ca2+ current also prevented mustard-oil-induced increases in Ca2+ permeation. It is interesting that fractional Ca2+ currents for wild-type and mutant TRPA1 were consistently higher than values predicted based on biionic reversal potentials using the Goldman-Hodgkin-Katz equation, suggesting that binding of Ca2+ in the pore hinders monovalent cation permeation. We conclude that the pore of TRPA1 is dynamic and supports a surprisingly large Ca2+ influx.

2-Aminoethoxydiphenyl Borate Alters Selectivity of Orai3 Channels by Increasing Their Pore Size

Stim1 in the endoplasmic reticulum and the three Orai (also termed CRACM) channels in the plasma-membrane are main components of native Ca(2+) release-activated Ca(2+) channels. A pharmacological hallmark of these channels is their distinct sensitivity to 2-aminoethoxydiphenyl borate (2-APB). Here we report that Orai3 currents can be robustly stimulated by 75 microm 2-APB independent of Stim1, whereas 2-APB at similar concentrations inhibited store-operated Orai1 currents. 2-APB did not only promote currents through Orai3 channels but also dramatically altered ion selectivity of Orai3 channels. This allowed for permeation of monovalent cations both in the inward as well as outward direction, which is in sharp contrast to the high Ca(2+) selectivity of store-operated Orai3 currents. An Orai3-R66W mutant, which lacked in analogy to the severe combined immune deficiency mutant Orai1-R91W store-operated activation, was also found to be resistant to 2-APB stimulation. The change in selectivity by 2-APB was associated with an increase in Orai3 minimum pore size from about 3.8A to more than 5.34 A. In line with a potential interaction of 2-APB with the Orai3 pore, among three pore mutants tested, the Orai3 E165Q mutant particularly resembled in its permeation properties those of 2-APB stimulated Orai3 and additionally exhibited a reduced response to 2-APB. In aggregate, stimulation of Orai3 currents by 2-APB occurred along with an alteration of the permeation pathway that represents a unique mechanism for regulating ion channel selectivity by chemical compounds.

Withdrawal period for Elancoban® for chickens for fattening, chickens reared for laying and turkeys for fattening - Scientific Opinion of the Panel on Additives and Products or Substances used in Animal Feed.

EFSA JournalVolume 6, Issue 7 730 OpinionOpen Access Withdrawal period for Elancoban® for chickens for fattening, chickens reared for laying and turkeys for fattening - Scientific Opinion of the Panel on Additives and Products or Substances used in Animal Feed European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author European Food Safety Authority (EFSA), European Food Safety Authority (EFSA)Search for more papers by this author First published: 09 July 2008 https://doi.org/10.2903/j.efsa.2008.730Citations: 2 Panel members: Georges Bories, Paul Brantom, Joaquim Brufau de Barberà, Andrew Chesson, Pier Sandro Cocconcelli, Bogdan Debski, Noël Dierick, Anders Franklin, Jürgen Gropp, Ingrid Halle, Christer Hogstrand, Joop de Knecht, Lubomir Leng, Anne-Katrine Lundebye Haldorsen, Alberto Mantovani, Miklós Mézes, Carlo Nebbia, Walter Rambeck, Guido Rychen, Atte von Wright and Pieter Wester Acknowledgement: The European Food Safety Authority wishes to thank the members of the Working Group on Coccidiostats for the preparation of this opinion. Adoption date: 18 June 2008 Published date: 9 July 2008 Question number: EFSA-Q-2007-140 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References Davison, K.L., 1984. Monensin Absorption and Metabolism in Calves and Chickens. J. Agr. Food Chem. 32, 1273– 1277. Dimenna, G.P., Lyon, F.S., Thompson, F.M., Creegan, J.A. and Wright, G.J., 1989. Effect of antibiotic combination, dosing period, dose vehicle, and assay method on salinomycin residue levels and their ionophoricity in chicken tissues. J. Agr. Food Chem. 37, 668– 676. 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SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process

In mammalian cells, active sodium transport and its derived functions (e.g., plasma membrane potential) are dictated by the activity of the Na(+),K(+)-ATPase (NK), whose regulation is essential for maintaining cell volume and composition, as well as other vital cell functions. Here we report the existence of a salt-inducible kinase-1 (SIK1) that associates constitutively with the NK regulatory complex and is responsible for increases in its catalytic activity following small elevations in intracellular sodium concentrations. Increases in intracellular sodium are paralleled by elevations in intracellular calcium through the reversible Na(+)/Ca(2+) exchanger, leading to the activation of SIK1 (Thr-322 phosphorylation) by a calcium calmodulin-dependent kinase. Activation of SIK1 results in the dephosphorylation of the NK alpha-subunit and an increase in its catalytic activity. A protein phosphatase 2A/phosphatase methylesterase-1 (PME-1) complex, which constitutively associates with the NK alpha-subunit, is activated by SIK1 through phosphorylation of PME-1 and its dissociation from the complex. These observations illustrate the existence of a distinct intracellular signaling network, with SIK1 at its core, which is triggered by a monovalent cation (Na(+)) and links sodium permeability to its active transport.